He was born at Reading, Berkshire and educated at Eton College and King's College, Cambridge. In 1782 he became fellow of King's College, and took orders, receiving the living of Holy Trinity Church, Cambridge, in the following year. He was at first so unpopular that services were frequently interrupted, and he was often insulted in the streets. Having overcome public prejudice, he subsequently gained a remarkable and lasting influence among the undergraduates of the university.

He became a leader among evangelical churchmen, was one of the founders of the Church Missionary Society in 1799, the London Society for Promoting Christianity Amongst the Jews (now known as the Church's Ministry Among Jewish People or CMJ) in 1809, and acted as adviser to the British East India Company in the choice of chaplains for India.

In 1792 he read An Essay on the Composition of a Sermon by the French Reformed minister Jean Claude. Simeon found that their principles were identical and used the essay as the basis for his lectures on sermon composition. Claude's essay also inspired Simeon to make clear his own theological position, the result being Horae Homileticae, his chief work.

He published hundreds of sermons and outlines of sermons (called "sermon skeletons"), still in print, that to some were an invitation to clerical plagiarism. His chief work is a commentary on the whole Bible, entitled Horae homileticae (London). The Simeon Trust was established by him for the purpose of acquiring church patronage to perpetuate evangelical clergy in Church of England parishes. It continues to operate to this day.

Charles Simeon is often hailed as something of an ancestor of the evangelical movement in the Church of England.

According to the historian Thomas Macaulay, Simeon's "authority and influence...extended from Cambridge to the most remote corners of England, ...his real sway in the Church was far greater than that of any primate." He is remembered in the Episcopal Church of the United States with a Lesser Feast and in the Anglican Church of Canada with a Commemoration on 12 November. In the Church of England he is remembered with a Lesser Festival on 13 November. His memorial by the monumental mason Hopper in Holy Trinity Church (Cambridge), was described by architectural critic Nikolaus Pevsner as an "epitaph in Gothic forms."